604-50-2|1-Methylquinazoline-2,4(1H,3H)-dione| Ambeed

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Quality Control of [ 604-50-2 ] Purity: 95% SDS Specification

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Product Details of [ 604-50-2 ]

CAS No. :	604-50-2
Formula :	C₉H₈N₂O₂
M.W :	176.17
SMILES Code :	O=C(N1)N(C)C2=C(C=CC=C2)C1=O
MDL No. :	MFCD00731030
InChI Key :	RWFOOMQYIRITHL-UHFFFAOYSA-N
Pubchem ID :	11788

Safety of [ 604-50-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 604-50-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	10
Fraction Csp3	0.11
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	50.09
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	54.86 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.42
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.31
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.23
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.92
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.7
Solubility	3.54 mg/ml ; 0.0201 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.02
Solubility	16.6 mg/ml ; 0.0944 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.7
Solubility	0.351 mg/ml ; 0.00199 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.15 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.66

Application In Synthesis of [ 604-50-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 604-50-2 ]

[ 604-50-2 ] Synthesis Path-Downstream 1~35

1
[ 590-28-3 ]
[ 119-68-6 ]
[ 604-50-2 ]

References: [1]Chemistry Letters,2005,vol. 34,p. 1438 - 1439.
[2]Chemistry of Heterocyclic Compounds,1996,vol. 32,p. 708 - 711.
[3]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1916,p. 17.
Chem.Abstr.,1917,vol. 11,p. 578.

2
[ 7505-81-9 ]
[ 541-41-3 ]
[ 604-50-2 ]

Yield	Reaction Conditions	Operation in experiment
5.27 g	In acetone; at 100℃; for 4h;Sealed tube;	Ethyl chloroformate (20 mL, 209 mmol) was added to 2-(methylamino)benzamide (10 g, 67 mmol). The vial was sealed and heated to 100 00 for 4h. The ethyl chloroformate was removed under vacuum and the residue loaded onto Biotage 50 g KP-Sil column (2 batches) and eluted with 20 - 100% EtOAc in cyclohexane followed by 0 - 20% MeOH in DCM. 1- methylquinazoline-2,4(1H,3H)-dione (5.27 g) was obtained as a white solid. LCMS (Method T2) Rt = 0.83 mins, mlz 177.06 [M+H].

References: [1]Organic Mass Spectrometry,1988,vol. 23,p. 816 - 820.
[2]Journal of the American Chemical Society,1954,vol. 76,p. 2459,2461.
[3]Patent: WO2018/215798,2018,A1 .Location in patent: Paragraph 00356.

3
[ 7505-81-9 ]
[ 57-13-6 ]
[ 604-50-2 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1889,vol. <2> 39,p. 142.

4
[ 119-68-6 ]
[ 57-13-6 ]
[ 604-50-2 ]

Yield	Reaction Conditions	Operation in experiment
64.3%	at 150℃; for 5h;	Urea (460 mmol) was heated to melt, then 2-methylaminobenzoic acid (46 mmol) was added. The mixture was stirred for 5 h at 150 C and then cooled to below 100 C. Water (70 mL) was added to quench the reaction. The precipitated was collected and recrystallized in a mixed solution of acetone (10 mL) and water (100 mL) to afford compound 1 as a white powder (5.25 g, 64.3%); mp 278-279 C; 1H NMR (DMSO-d6) delta (ppm): 3.43 (s, 3H), 7.26 (t, J = 12 Hz, 1H), 7.41 (d, J = 12 Hz, 1H), 7.75 (t, J = 15 Hz, 1H), 7.98 (d, J = 6 Hz, 1H), 11.54 (s, 1H). ESI-MS (m/z): 177 (M+H)+.

References: [1]Chemistry Letters,2005,vol. 34,p. 1438 - 1439.
[2]Medicinal Chemistry Research,2014,vol. 23,p. 2169 - 2177.
[3]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 3405 - 3413.
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1916,p. 17.
Chem.Abstr.,1917,vol. 11,p. 578.
[5]European Journal of Medicinal Chemistry,2018,vol. 152,p. 560 - 569.

5
[ 2969-81-5 ]
[ 604-50-2 ]
[ 172751-14-3 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 2 - 9.

6
[ 77-78-1 ]
C₈H₅N₂O₂^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 607-19-2 ]
[ 604-50-2 ]

References: [1]Chemistry of Heterocyclic Compounds,1996,vol. 32,p. 708 - 711.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 4 (2R)-(4'-Chlorobiphenyl-4-sulfonylamino)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)pentanoic Acid The title compound is obtained as a white solid analogously as described in Example 1: m.p. 188-191 C.; NMR(DMSO-d6) 1.44-1.68 (m, 4H), 3.47 (s, 3H), 3.67-3.78 (m, 1H), 3.79-3.89 (m, 2H), 7.27 (t, 1H, J=7.5), 7.40 (d, 1H, J=8.6), 7.52 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.5), 7.67-7.79 (m, 1H), 7.81 (s, 4H), 8.01 (d, 1H, J=6.8), 8.20 (d, 1H, J=8.8), 12.62 (br s, 1H); IR 1734, 1702, 1627, 1337, 1164; ESI-MS 540 (M--1), 542 (M++1). 1,2,3,4-Tetrahydro-1-methyl-2,4-dioxoquinazoline is prepared as follows:
		EXAMPLE 4 (2R)-(4'-Chlorobiphenyl-4-sulfonylamino)-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)pentanoic acid The title compound is obtained as a white solid analogously as described in Example 1: m.p. 188-191 C.; NMR(DMSO-d6) 1.44-1.68 (m, 4H), 3.47 (s, 3H), 3.67-3.78 (m, 1H), 3.79-3.89 (m, 2H), 7.27 (t, 1H, J=7.5), 7.40 (d, 1H, J=8.6), 7.52 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.5), 7.67-7.79 (m, 1H), 7.81 (s, 4H), 8.01 (d, 1H, J=6.8), 8.20 (d, 1H, J=8.8), 12.62 (br s, 1H); IR 1734, 1702, 1627, 1337, 1164; ESI-MS 540 (M--1), 542 (M++1). 1,2,3,4-Tetrahydro-1-methyl-2,4-dioxoquinazoline is prepared as follows:

9
[ 74-88-4 ]
sodium compound of N_.N'-benzoylen-urea [ No CAS ]
[ 604-50-2 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1889,vol. <2> 39,p. 142.

10
[ 86-96-4 ]
methylating agent [ No CAS ]
[ 607-19-2 ]
[ 604-50-2 ]

References: [1]Chemistry of Heterocyclic Compounds,1996,vol. 32,p. 708 - 711.

11
[ 7664-93-9 ]
5-methyl-11-oxo-11<i>H</i>-pyrido[2,1-<i>b</i>]quinazolinium; iodide [ No CAS ]
permanganate [ No CAS ]
[ 604-50-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1924,vol. 440,p. 321.

12
[ 604-50-2 ]
4-(1-methyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazol-3-yl)butanoic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 2 - 9.

13
[ 10328-92-4 ]
[ 604-50-2 ]

References: [1]Organic Mass Spectrometry,1988,vol. 23,p. 816 - 820.

Yield	Reaction Conditions	Operation in experiment
62%		A mixture of methyl 2-methylaminobenzoate (4.95 g, 30 mmol), sodium isocyanate (3.9 g, 60 mmol) and acetic acid (30 mL) is stirred at RT for 24 h. The precipitated product is collected by vacuum filtration, washed with water and diethyl ether and dried to give 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (3.25 g, 62%) as a white solid.
62%		A mixture of methyl 2-methylaminobenzoate (4.95 g, 30 mmol), sodium isocyanate (3.9 g, 60 mmol) and acetic acid (30 mL) is stirred at RT for 24 h. The precipitated product is collected by vacuum filtration, washed with water and diethyl ether and dried to give 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (3.25 g, 62%) as a white solid.

15
[ 604-50-2 ]
[ 240135-69-7 ]
(2R)-t-Butoxycarbonylamino-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)pentanoic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide;	A (2R)-t-Butoxycarbonylamino-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)pentanoic Acid t-Butyl Ester Sodium hydride (0.408 g, 10.2 mmol) was added to a solution of <strong>[604-50-2]1,2,3,4-tetrahydro-<strong>[604-50-2]1-methyl-2,4-dioxoquinazoline</strong></strong> (2.17 g, 12.4 mmol) and 18-crown-6 (0.045 g) in 25 mL of DMF. After stirring at RT for 30 min, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (3.60 g, 9.02 mmol) in 15 mL of DMF was added, and the solution was stirred at RT for 30 min, then at 60 C. for 6 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 0.05M aqueous HCl. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane/ethyl acetate 3/1~2/1) to give the title compound (3.81 g, 95% yield): NMR (400 MHz, CDCl3) 1.42 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.60 (s, 3H), 4.08-4.21 (m, 3H), 5.06 (br d, 1H, J=8.1 Hz), 7.19-7.31 (m, 2H), 7.68 (dt, 1H, J=7.84, 1.56 Hz), 8.22 (dd, 1H, J=7.88,1.52 Hz).
95%	In N,N-dimethyl-formamide;	A. (2R)-t-Butoxycarbonylamino-5-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)pentanoic acid t-butyl ester Sodium hydride (0.408 g, 10.2 mmol) was added to a solution of <strong>[604-50-2]1,2,3,4-tetrahydro-<strong>[604-50-2]1-methyl-2,4-dioxoquinazoline</strong></strong> (2.17 g, 12.4 mmol) and 18-crown-6 (0.045 g) in 25 mL of DMF. After stirring at RT for 30 min, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (3.60 g, 9.02 mmol) in 15 mL of DMF was added, and the solution was stirred at RT for 30 min, then at 60 C. for 6 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 0.05M aqueous HCl. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane/ethyl acetate 3/1~2/1) to give the title compound (3.81 g, 95% yield): NMR (400 MHz, CDCl3) 1.42 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.60 (s, 3H), 4.08-4.21 (m, 3H), 5.06 (br d, 1H, J=8.1 Hz), 7.19-7.31 (m, 2H), 7.68 (dt, 1H, J=7.84, 1.56 Hz), 8.22 (dd, 1H, J=7.88, 1.52 Hz).

References: [1]Patent: US6410580,2002,B1 .
[2]Patent: US6277987,2001,B1 .

16
[ 604-50-2 ]
1-methyl-3-trichloromethylthio-2,4-dioxo-1,3-dihydroquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;	EXAMPLE 8 Following the method of Example 1 but substituting 1.76 g (0.01 mole) 1-methyl-2,4-dioxo-1,3-dihydroquinazoline for the 3-methyl-2,4-dioxo-1,3-dihydroquinazoline and using 0.40 g (0.01 mole) sodium hydroxide there was obtained 1.2 g (38%) of 1-methyl-3-trichloromethylthio-2,4-dioxo-1,3-dihydroquinazoline having a melting point of 194-195 C. The NMR spectrum of the compound confirms the structure.

References: [1]Patent: US4551458,1985,A .

17
[ 246264-25-5 ]
[ 604-50-2 ]
[ 246264-31-3 ]

Yield	Reaction Conditions	Operation in experiment
72%		(1) (+-)-N-Methyl-2-[2-(1-methylquinazolin-2,4-dione-3-yl]ethyl)-N-(4-phenoxybenzenesulfonyl)glycine allyl ester In a similar manner to that described in Example 1(1), a reaction was carried out using (+-)-2-(2-hydroxyethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester, the product of Example 41(2), instead of(+-)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using <strong>[604-50-2]1-methylquinazoline-2,4-dione</strong>, instead of phthalimide, to afford the desired compound (yield 72%) as a white powder. 1H-Nuclear magnetic resonance spectrum (270 MHz, CDCl3) delta ppm: 8.22-8.19 (1H, m), 7.79-7.66 (3H, m), 7.43-7.36 (2H, m), 7.29-7.18 (3H, m), 7.07-6.99 (4H, m), 5.81-5.67 (1H, m), 5.27-5.18 (2H, m), 4.83 (1H, dd, J=10Hz, 5Hz), 4.47-4.37 (2H, m), 4.24-4.06 (2H, m), 3.60 (3H, s), 2.99 (3H, s), 2.35-2.22 (1H, m), 2.15-2.00 (1H, m).

References: [1]Patent: EP1069110,2001,A1 .

18
[ 542-69-8 ]
[ 604-50-2 ]
[ 5544-30-9 ]

References: [1]Chemistry of Heterocyclic Compounds,2009,vol. 45,p. 1508 - 1514.

19
[ 119-68-6 ]
[ 917-61-3 ]
[ 604-50-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With acetic acid; sodium hydroxide; In water; at 75℃; for 4h;	Sodium cyanate (28mmol) in water (25mL) was added to a solution of N-methyl anthranilic acid (20mmol) and acetic acid (0.2mL) in water (50mL) with stirring. When the temperature of the reaction mixture reached 40C, NaOH was added in portions till the reaction temperature reach to 75C. Stirring was continued without cooling for 4h, after which the crystals were filtered off and dissolved in boiling water (50mL). The solution was acidified with 50% H2SO4 to pH 1-2. The precipitated crystals were filtered off, washed with water and recrystallized from 50% acetic acid to give compound 2 (2.92g, 84%); m p 278C [24].
77%		Sodium cyanate (30.15 g, 0.46 mol) was added to a slurry of N- methylanthranilic acid (50.0 g, 0.33 mol) in water (1 .75 L) and acetic acid (3.3 mL). The reaction mixture was heated to 50 C for 1 h. The solution was slowly basified by the addition of sodium hydroxide (exothermic). The resulting solution was heated to 80 C and stirred overnight. The reaction mixture was cooled to 0 C and the resultant precipitate collected by filtration. The solid was dissolved in boiling water (200 mL) and acidified with cone, sulfuric acid to pH 2. The slurry was cooled to room temperature and filtered. The solid was dried in a vacuum oven to give 1 -methylquinazoline-2,4(1 H,3H)-dione (53 g, 0.30 mol, 77%).1 H NMR (300MHz, DMSO-d6) delta = 1 1 .54 (br. s., 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.77 (t, J = 7.9 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 7.28 (t, J = 7.5 Hz, 1 H), 3.33 (s, 3H)
69%	With acetic acid; sodium hydroxide; In water; at 40 - 75℃; for 4h;	2-(Methylamino)benzoic acid (4.50 g, 0.0300 mol) and acetic acid (0.3 mL) were dissolved in water (158 mL), a solution of sodium isocyanate (2.76 g, 42.0 mmol) in water (54 mL) was added slowly at room temperature. The reaction mixture was heated to 40C and added with sodium hydroxide (34.8 g, 0.870 mol). The temperature was raised to 75C and the reaction solution was stirred for 4 hours, cooled to room temperature, filtered and the filter cake was dissolved in boiling water (10 mL). The system was adjusted to pH 1-2 with 50% sulfuric acid solution (15 mL), filtered and the filter cake was washed with a small amount of water (3 mL) and dried under reduced pressure to give 1-methylquinazoline-2,4-dione (3.64 g, as a yellow solid) with a yield of 69%. 1H NMR: (400 MHz, DMSO-d6) delta 11.55(s, 1H), 8.00(d, J = 8.0 Hz, 1H), 7.78(t, J = 8.0 Hz, 1H), 7.42(d, J = 8.0 Hz, 1H), 7.28(t, J = 8.0 Hz, 1H), 3.44(s, 3H). MS-ESI calcd. [M + H]+ 177, found 177.

References: [1]Chemistry of Heterocyclic Compounds,2009,vol. 45,p. 1508 - 1514.
[2]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2013,vol. 110,p. 324 - 332.
[3]Patent: WO2016/92326,2016,A1 .Location in patent: Page/Page column 97; 113.
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 10767 - 10792.
[5]Patent: EP3299371,2018,A1 .Location in patent: Paragraph 0525; 0526.
[6]Letters in drug design and discovery,2014,vol. 11,p. 712 - 720.

20
[ 604-50-2 ]
[ 1232775-11-9 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; at 50℃;	1 -Methylquinazoline-2,4(1 H,3H)-dione (25 g, 0.142 mol) was added portionwise to chlorosulfonic acid (125 mL, 1 .88 mol) at 50 C. The reaction mixture was heated to 50 C and stirred overnight then allowed to cool. The reaction mixture was added carefully to ice/water (1 .5 L) maintaining the temperature <20 C. The resultant precipitate was collected by filtration and dried in an open atmosphere to give 1 -methyl- 2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride as a white powder (44 g, 0.16 mol, 1 13% - contains water).1H NMR (300MHz, DMSO-d6) delta = 1 1 .57 (s, 1 H), 8.19 (d, J = 2.1 Hz, 1 H), 7.91 (dd, J = 2.2, 8.7 Hz, 1 H), 7.38 (d, J = 8.7 Hz, 1 H)

References: [1]Chemistry of Heterocyclic Compounds,2009,vol. 45,p. 1508 - 1514.
[2]Patent: WO2016/92326,2016,A1 .Location in patent: Page/Page column 97; 113.
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 10767 - 10792.

21
[ 604-50-2 ]
[ 1232775-13-1 ]

References: [1]Chemistry of Heterocyclic Compounds,2009,vol. 45,p. 1508 - 1514.

22
[ 604-50-2 ]
[ 107-08-4 ]
[ 1232775-32-4 ]

References: [1]Chemistry of Heterocyclic Compounds,2009,vol. 45,p. 1508 - 1514.

23
[ 604-50-2 ]
[ 98-88-4 ]
[ 1296731-98-0 ]

References: [1]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1380 - 1385.

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[ 874-60-2 ]
[ 1296732-00-7 ]

References: [1]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1380 - 1385.

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[ 100-07-2 ]
[ 1296732-02-9 ]

References: [1]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1380 - 1385.

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[ 122-04-3 ]
[ 1296732-06-3 ]

References: [1]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1380 - 1385.

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[ 586-75-4 ]
[ 1296732-04-1 ]

References: [1]Chemistry of Heterocyclic Compounds,2011,vol. 46,p. 1380 - 1385.

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[ 1422209-99-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	General procedure: Procedure g : alkylation pf^qumazolinediones with mesylates or halpgenides :.A solution of the quinazolinedione (1.0 mmol), mesylate (1 mmol) or halogenide (1 mmol) and CS2CO3 (1.2 mmol) in dry DMF (5 ml) is stirred at rt for 12 h. The reaction mixture is diluted with water and EA and the phases are separated. The aq. layer is extracted two more times with EA and the combined org. layers are washed with water (3x) and brine, dried over MgS04 and concentrated under reduced pressure. The residue is dissolved in EA and crystallized from TBME or purified by CC.; L. i. 3 -allyl-1 -methyl- lH-quinazoline-2, 4-dione:Starting from l-methylquinazoline-2,4(lH,3H)-dione and allyl bromide and using Procedure E, the title intermediate was obtained as a colourless solid (0.125 g; 58% yield). 1H NMR (CDC13) delta: 8.03 (dd, J = 7.9, 1.6 Hz, 1H), 7.77 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.29 (m, 1H), 5.85 (m, 1H), 5.12 (m, 1H), 5.07 (t, J = 1.5 Hz, 1H), 4.53 (dt, J = 5.3, 1.5 Hz, 2H), 3.50 (s, 3H).

References: [1]Patent: WO2013/21363,2013,A1 .Location in patent: Page/Page column 56; 65.

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